1. Field of the Invention
The present invention relates to diarylbenzopyran derivatives or their pharmaceutically acceptable salts and cyclooxygenase-2 inhibitor composition containing same.
2. Description of the Related Arts
Non-steroidal, antiinflammatory drugs(NSAIDs), which have been most prevalently used all over the world, have a problem of causing serious side-effects such as gastrointestinal tract or nephro-toxicity. NSAIDs inhibit the activity of cyclooxygenase(hereinafter xe2x80x9cCOXxe2x80x9d), which is an enzyme involved in prostagladin synthesis, resulting in the inhibition of the biosynthesis of prostaglandin not only in inflammatory loci but also in stomach and kidney. It has been found that COX exists in the form of isoenzymes: COX-1 and COX-2[Cell, 83,345, (1995)]. COX-1 exists in normal cells and keeps cell homeostasis and controlls the function of stomach and kidney, while COX-2 is expressed by mitogens or cytokines in pain sites where inflammation and other imrunoreactions occur [J. Biol. Chem., 271,33157(1996)] and is involved in pathologic phenomenon. Therefore the toxicity of NSAIDs is due to its inhibition of the coexisting COX-1""s.
To avoid this problem, selective inhibitors of COX-2 has been investigated [Nature, 367, 215(1995)]. The selective inhibitors (i) have suitable antiinflammation, pain-relieving action, antipyretic action; (ii) remove toxicity from and reduce bleeding time in gastrointestinal tract and kidney; (iii) show potential anticancer activity and reduce the induction of mechanism-related side-effect; and also (iv) lower the induction of asthma in asthmatic patients who are sensitive to conventional NSAIDs. These selective inhibitors of COX-2 also show inhibition effect on smooth muscle constriction and could be used in treating Alzheimer""s disease and osteoporosis of women after menopausa.
Active researches have been made on the selective inhibitors of COX-2. For example, WO 9606840, Bioorg, Med. Chem. Lett. 5, 2377(1995), Ann. Report. Med. Chem., 211(1997) and many other publications report COX-2 inhibitors having heterocyclic moiety as a base structure.
The present inventors made extensive researches to provide a new compound capable of inhibiting the COX-2""s action selectively and strongly, and as a result found out that the diarylbenzopyran derivatives fulfill the requirements.
Therefore, an object of the present invention is to provide diarylbenzopyran derivatives represented by the following general formula (I): 
wherein
Y is an oxygen atom or a sulfur atom;
R1 and R2, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl group;
R3 is a group of a formula: S(O)nR5 wherein n is an integer of 0xcx9c2, R5 is a hydrogen atom, a C1-C6 lower alkyl group, or a group of a formula: NR6R7 wherein R6 and R7, identical to or different from each other, are independently a hydrogen atom, or a C1-C6 lower alkyl group; and
R4 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C1-C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group presented by the following structures: 
wherein
R8 through R12, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a nitro group, a group of a formula: S(O)nR5xe2x80x2 a group of a formula: NR6R7, a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R5, R6 and R7 have the same meaning as defined by R3 above; and
R13 is a hydrogen atom, a halogen atom, A C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a trifluoromethoxy group, a carboxyl group, or an acetyl group;
Another object of the present invention is to provide a cyclooxygenase-2-inhibitor-composition comprising an effective amount of a compound represented by the above general formula(I) or a pharmaceutically acceptable salt thereof.
The diarylbenzopyran derivatives or their pharmaceutically acceptable salts of the present invention effectively and selectively inhibit COX-2""s action of biosynthesizing the prostagladin, which plays a more important role in progress of inflammation than COX-1.
The diarylbenzopyran derivatives of the present invention, which are useful as selective COX-2""s inhibitor drugs, are represented by the following general formula(I) 
wherein
Y is an oxygen atom or a sulfur atom;
R1 and R2, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl group;
R3 is a group of a formula: S(O)nR5 wherein n is an integer of 0xcx9c2, R5 is a hydrogen atom, a C1-C6 lower alkyl group, or a group of a formula: NR6R7 wherein R6 and R7, identical to or different from each other, are independently a hydrogen atom, or a C1-C6 lower alkyl group;
R4 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C1-C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group presented by the following structures: 
wherein
R8 through R12, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluromethyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a nitro group, a 3,4-methylenedioxy group, a group of a formula: S(O)nR5, a group of a formula: NR6R7, a trifluromethoxy group, a nitrile group, a carboxyl group, an acetyl group, or a formyl group, wherein n, R5, R6 and R7 have the same meaning as defined X and R3 above; and
R13 is a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluromethyl group, a alkoxy group, a hydroxy group, a trifluromethoxy group, a carboxyl group, or an acetyl group.
Also, the diarylbenzopyran derivatives of the above-described general formula(I) could form pharmaceutically acceptable salts, which generally refer to the salts that could form alkaline-metal salts, acid-addition salts, or base-addition salts and are pharmaceutically acceptable because of their non-toxicity. The pharmaceutically acceptable acid-addition salts of the compound(I) are derived from the organic acid or inorganic acid. The inorganic acid used in the present invention, for example, is hydrochloric acid, bromic acid, iodic acid, nitric acid, carbonic acid, sulfuric acid or phosphoric acid. The organic acid used in the present invention, for example, is formic acid, acetic acid, propionic acid, succinic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, methylsulfonic acid, p-toluenesulfonic acid or salicylic acid.
The pharmaceutically acceptable base-addition salts of the compound(I) are metal salts derived from Al, Ca, Li, Mg, K, Na and Zn or organic salts derived from N, Nxe2x80x2-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
Even though the use of diarylbenzopyran derivatives(I) of the present invention is not particulary limited, it is useful for treating, for example inflammatory diseases, or as analgesia for labor pain, headache or as antifebrile. The compound(I) of the present invention, not particularly limited, is also useful for treating arthritis such as rheumatic arthritis, spondylitis ankylopoietica, gouty arthritis, osteoarthritis. And the compound(I) of the present invention is useful for treating asthma, bronchitis, dysmenorrhea, tendinitis, bursitis and also useful for treating skin-related diseases such as psoriasis, eczema, bum and dermatitis. Also, the compound(I) of the present invention is useful for treating diseases such as peptic ulcer, gastritis, topical enteritis, colic diverticulitis, gastrointestinal bleeding, and the like. Also the compound(I) of the present invention coud be used in treating cancer by inhibiting the transformation of cell and the growth of metastatic cancer. Moreover, it could be used in treating and preventing diseases, which show abnormality in cyclooxygenase-involving proliferation such as diabetic retinopathy and cancerous vascularization. And it is effective in treating Alzheimer""s disease and used in preventing osteoporosis and in treating glaucoma.
Also, the compound(I) of the present invention can be used as a substitute drug for conventional non-steroidal antiinflammatory drugs because it shows high activity and specificity on COX-2. Particulary, the compound of the present invention could be used as a substitute drug in treating patients who are suffering from hypoprothrombinemia, hemophilia or kidney disease, or waiting for surgery or has recurrent gastrointestinal tract disorders such as agglutination abnormality cause by anticoagulant uptake.
In addition to that the compound of the present invention, as we described above, is useful for treating human diseases, it also could be used in treating warm-blooded animals such as mice, house mice, horses, lambs, dogs, cats and etc.
Also, the compound (I) of the present invention can be used for substituting all or parts of active ingredients in the existing non-steroidal inflammatory preparations. In other words, diarylbenzopyran derivatives or their pharmaceutically acceptable salts could be used alone or combined with one of or some of the following components:
(i) pain relievers containing acetoaminophen or phenacetin;
(ii) potentiators containing caffeine;
(iii) H2-antagonists;
(iv) decongestants containing aluminum hydroxide, magnesium hydroxide, simethicone, phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, propylhexedrine or levodeoxyephedrine;
(v) antitussives containing codeine, hydrocodone, caramiphene, carbetapentane or dextramethorphan;
(vi) prostaglandins containing misoprostol, enprostil, riprostil, ornoprostol or rosaprostol;
(vii) diuretics;
(viii) antihistamines having or without having sedative action:
The preferred compound(I) of the present invention includes one of the following compounds:
2-(4-(Methylsulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one,
3-(2-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-(N,N-Dimethylamino)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-(N-Methylamino)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethoxyphenyl)-4H-1-benzopyran-4-one,
3-(3-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Isopropylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Ethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Hydroxymethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethylphenyl)-4H-1-benzopyran-4-one,
3-(4-Hydroxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2,3-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3,5-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2Hydroxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2,4-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Acetylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2,4-Dimethylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Formylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Carboxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Chloro-3-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-5-methoxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-5-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3,5-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(N-methyl-3-pyrazolyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
6-Chloro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(methylsulfonyl)phenyl)-3-(3-nitrophenyl)-4H-1-benzopyran-4-one,
3-(3,4-Difluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(methylsulfonyl)phenyl)-3-(1-naphthyl)-4H-1-benzopyran-4-one,
3-(3-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3-Chloro-4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Bromophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2,3-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(3-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-oxazolyl)-4H-1-benzopyran-4-one,
6-Fluoro-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Benzo[b]thienyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Chloro-5-pyridinyl)-7-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
7-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(4-pyridinyl)-4H-1-benzopyran-4-one,
6-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
7-Fluoro-3-(2-methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-((3,4-methylenedioxy)phenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-thiazolyl)-4H-1-benzopyran-4-one,
3-(Benzofuran-2-yl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-thienyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-pyrazinyl)-4H-1-benzopyran-4-one,
3-(2-Methyl-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
6-Fluoro-3-(2-methyl-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
6-Fluoro-3-(2-methoxy-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Chloro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Chloro-5-pyridinyl)-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
6-fluoro-3-(2-fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
7-fluoro-3-(2-fluoro-5-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-6-methoxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-(2-trifluoromethyl-5-pyridinyl)-4H-1-benzopyran-4-one,
3-(2-Fluoro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Chloro-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(5-Bromo-3-pyridinyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(2-Furyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(5-Indanyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
3-(4-Fluorophenyl)-6-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-methylphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3,4-difluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(4-chloro-3-fluorophenyl)-4H-1 benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-chloro-4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3,4-dichlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-chlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-chlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(4-chlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-((4-methylthio)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-((3,4-methylenedioxy)phenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2,3-difluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2,4-difluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-methylphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-methoxyphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(4-methylphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(4-methoxyphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-methoxyphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-7-fluoro-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3,5-difluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-chloro-5-pyridinyl)-6-fluoro-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-fluoro-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-methyl-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(2-methoxy-5-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Arninosulfonyl)phenyl)-3-(4-pyridinyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-thienyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-3-(2-furyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-phenyl-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-methylphenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-chlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(2-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3,4-dichlorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-8-chloro-3-(4-fluorophenyl)-5-hydroxy-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-8-chloro-3-(4-fluorophenyl)-5-methoxy-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-methoxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-7-methoxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Aminosulfonyl)phenyl)-6-hydroxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one,
2-(4-(Methylsulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-thione,
3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
6-Fluoro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(2-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
7-Fluoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,
3-(3-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(2-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(4-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(3-Methylphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(4-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
6-Fuoro-2-(4-(methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,
3-(2-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(2,3-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(3,4-Dichlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(3-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(4-Chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
3-(3-Methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
2-(4-(Methylsulfonyl)phenyl)-3-(4-trifluoromethylphenyl)-4H-1-benzopyran-4-thione,
3-(3-Chloro-4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-thione,
2-(4-(Methylsulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-3-(3-pyridinyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-3-(2-fluorophenyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-3-(4-chlorophenyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-3-phenyl-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-6-fluoro-3-(4-fluorophenyl)-4H-1-benzopyran-4-thione,
2-(4-(Aminosulfonyl)phenyl)-7-fluoro-3-(3-pyridinyl)-4H-1-benzopyran-4-thione
The diarylbenzop,ran derivatives of the present invention can be prepared by reaction schemes 1 through 6. Wherein R1, R2, R3 and R4 in the reaction schems have the same meanings as defined above.
[Reaction Scheme 1]
It represents a four-step reaction of preparing diarylbenzopyran derivative. In Step 1, chalcone(3) is prepared by condensation of substituted acetophenon(1) and substituted aldehyde(2) in the presence of KOH base. In Step 2, flavone derivative is prepared by cyclization of calcone(3) by adding I2 as a catalyst. A suitable solvent of this step is dimethyl sulfoxide(DMSO). In Step 3, 3-halogenized flavone derivative is prepared by reaction of flavone derivative(4) either with I2 or N-bromosuccinimide(NBS). In Step 4, benzopyran derivative(7) in which R4 group at position 3 is substituted is prepared by cross-coupling reaction of substituted flavone derivative(5) with R4 group substituted boronic acid using Paladium as a catalyst[(Synth. Commun., 11, 513(1981)].
[Reaction Scheme 2]
It represents a 3-step transformed reaction of preparing diarylbenzopyran derivative. In Step 1, compound(8) is prepared by the reaction of flavone derivative(4) having methylthio group as R3 with I2 in the presence of Lithium diisopropylamide(LDA) base, at a temperature of xe2x88x9278xc2x0 C. [J. Chem. Soc. Perkin Trans. I. 799(1985)]. In Step 2, methylsulfonylflavone(10) is prepared by oxidation with oxone(potassium peroxymonosulfate) or 3-chloroperoxybenzoic acid(MCPBA). In Step 3, benzopyran derivative(11) is prepared by cross-coupling reaction of compound(10) with boronic acid(6) using paladium as catalyst.
Alternatively, compound(11) could be prepared by the following method: First, methylsulfonyl group substituted flavone derivative(9) is prepared by oxidizing compound(4) having methylthio group as R3 with oxone; and then compound(10) is prepared by reacting compound(9) with I2 and [Bis(trifluoroacetoxy)iodo]benzene(BTI); and benzopyran derivative(11) is prepared by Step 3 of the above reaction.
[Reaction Scheme 3]
It represents the 3-step modified reaction of preparing diarylbenzopyran derivative. In Step 1, bromoflavone(12) is prepared by refluxing flavone derivative(4) having methylthio group as R3 in chloroform in the presence of N-bromosuccinimide(NBS). In Step 2, methylsulfonylflavone(13) is prepared by oxidation with oxone or MCPBA. In Step 3, benzopyran derivative(11) is substituted is prepared by cross-coupling reaction of compound(13) with boronic acid(6) using paladium catalyst.
[Reaction Scheme 4]
It represents the 1-step reaction of preparing diarylbenzopyranthione derivative. Benzopyranthione derivative(14) is prepared by refluxing diarylbenzopyran derivative with Lawesson reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphentan-2,4-disulfate; Org. Synth. Coll., 7, 372(1990)) or P4S10 in toluenet.
[Reaction Scheme 5]
It represents the 3-step reaction of preparing diarylbenzopyran derivative. In Step 1, methylsulfinylflavone derivative(15) is prepared by oxidizing compound(5) with oxone or MCPBA. In Step 2, aminosulfonylflavone derivative is prepared by reacting flavone derivative(15) with trifluoroacetic anhydride(TFAA), chlorine gas, ammonium hydroxide. In Step 3, benzopyran derivative(17) is prepared by cross-coupling reaction of aminosulfonylflavone deriative(16) with boronic acid(6) using paladium catalyst.
[Reaction Scheme 6]
It represents the modified reaction of preparing diarylbenzopyran derivative. In Step 1, benzopyran derivative(18) is prepared by cross-coupling reaction of flavone derivative(15) prepared in reaction scheme 5, Step 1 with boronic acid(6) using paladium catalyst. In next step, benzopyran derivatives(17) is prepared by having the same condition of the reaction scheme 5, Step 2.